{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:53:18Z","timestamp":1790394798632,"version":"4.1.0"},"reference-count":43,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T00:00:00Z","timestamp":1629417600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008433","name":"Consejer\u00eda de Educaci\u00f3n, Juventud y Deporte, Comunidad de Madrid","doi-asserted-by":"publisher","award":["B2017\/BMD3813 ELA-Madrid"],"award-info":[{"award-number":["B2017\/BMD3813 ELA-Madrid"]}],"id":[{"id":"10.13039\/501100008433","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CIBERNED CB18\/05\/00040"],"award-info":[{"award-number":["CIBERNED CB18\/05\/00040"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004587","name":"Instituto de Salud Carlos III","doi-asserted-by":"publisher","award":["CIBERNED CB06\/05\/0089"],"award-info":[{"award-number":["CIBERNED CB06\/05\/0089"]}],"id":[{"id":"10.13039\/501100004587","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["RTI2018-096100-B-I00"],"award-info":[{"award-number":["RTI2018-096100-B-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["PID2019-105600RB-I00"],"award-info":[{"award-number":["PID2019-105600RB-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100011033","name":"Agencia Estatal de Investigaci\u00f3n","doi-asserted-by":"publisher","award":["RTI2018-0988885-B-I00"],"award-info":[{"award-number":["RTI2018-0988885-B-I00"]}],"id":[{"id":"10.13039\/501100011033","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyotrophic Lateral Sclerosis (ALS) is the most common degenerative motor neuron disease in adults. About 97% of ALS patients present TDP-43 aggregates with post-translational modifications, such as hyperphosphorylation, in the cytoplasm of affected cells. GSK-3\u03b2 is one of the protein kinases involved in TDP-43 phosphorylation. Up-regulation of its expression and activity is reported on spinal cord and cortex tissues of ALS patients. Here, we propose the repurposing of Tideglusib, an in-house non-ATP competitive GSK-3\u03b2 inhibitor that is currently in clinical trials for autism and myotonic dystrophy, as a promising therapeutic strategy for ALS. With this aim we have evaluated the efficacy of Tideglusib in different experimental ALS models both in vitro and in vivo. Moreover, we observed that GSK-3\u03b2 activity is increased in lymphoblasts from sporadic ALS patients, with a simultaneous increase in TDP-43 phosphorylation and cytosolic TDP-43 accumulation. Treatment with Tideglusib decreased not only phospho-TDP-43 levels but also recovered its nuclear localization in ALS lymphoblasts and in a human TDP-43 neuroblastoma model. Additionally, we found that chronic oral treatment with Tideglusib is able to reduce the increased TDP-43 phosphorylation in the spinal cord of Prp-hTDP-43A315T mouse model. Therefore, we consider Tideglusib as a promising drug candidate for ALS, being proposed to start a clinical trial phase II by the end of the year.<\/jats:p>","DOI":"10.3390\/ijms22168975","type":"journal-article","created":{"date-parts":[[2021,8,20]],"date-time":"2021-08-20T08:44:45Z","timestamp":1629449085000},"page":"8975","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":70,"title":["Tideglusib, a Non-ATP Competitive Inhibitor of GSK-3\u03b2 as a Drug Candidate for the Treatment of Amyotrophic Lateral Sclerosis"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4593-4889","authenticated-orcid":false,"given":"Loreto","family":"Mart\u00ednez-Gonz\u00e1lez","sequence":"first","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas, CSIC, Calle Ramiro Ma\u00e9tzu 9, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Gonzalo-Consuegra","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Neuroqu\u03afmica, Departamento de Bioqu\u03afmica y Biolog\u03afa Molecular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"G\u00f3mez-Almer\u00eda","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Neuroqu\u03afmica, Departamento de Bioqu\u03afmica y Biolog\u03afa Molecular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gracia","family":"Porras","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas, CSIC, Calle Ramiro Ma\u00e9tzu 9, 28040 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"de Lago","sequence":"additional","affiliation":[{"name":"Instituto de Investigaci\u00f3n en Neuroqu\u03afmica, Departamento de Bioqu\u03afmica y Biolog\u03afa Molecular, Facultad de Medicina, Universidad Complutense de Madrid, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3416-9440","authenticated-orcid":false,"given":"\u00c1ngeles","family":"Mart\u00edn-Requero","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas, CSIC, Calle Ramiro Ma\u00e9tzu 9, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2707-8110","authenticated-orcid":false,"given":"Ana","family":"Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Centro de Investigaciones Biol\u00f3gicas Margarita Salas, CSIC, Calle Ramiro Ma\u00e9tzu 9, 28040 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red Sobre Enfermedades Neurodegenerativas (CIBERNED), Instituto de Salud Carlos III, 28031 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,8,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"352","DOI":"10.1007\/s13311-015-0338-x","article-title":"TDP-43 Proteinopathy and ALS: Insights into Disease Mechanisms and Therapeutic Targets","volume":"12","author":"Scotter","year":"2015","journal-title":"Neurotherapeutics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1038\/nn.2779","article-title":"Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43","volume":"14","author":"Polymenidou","year":"2011","journal-title":"Nat. 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